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Chronic Lymphocytic LeukemiaPhase 1/2CORONADO CLLNCT05405309

RP-3500 and Olaparib in DNA Damage Repair Pathway Deficient Relapsed/Refractory Chronic Lymphocytic Leukemia

A Phase 1/2 study testing RP-3500 and Olaparib in people with Chronic Lymphocytic Leukemia, run by University of Utah at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

This is an open-label, multicenter, phase Ib/II study of the combination of RP-3500 and olaparib in Relapsed/Refractory Chronic Lymphocytic Leukemia (R/R CLL) patients with DDR deficiencies. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Chronic Lymphocytic Leukemia
What is being tested?
RP-3500 and Olaparib
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
5 participants
Where
1 siteUnited States
Study dates
23 Sep 2022to 10 Jan 2025
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Diagnosis of Chronic lymphocytic leukemia (CLL) according to the National Cancer Institute International Workshop on Chronic Lymphocytic Leukemia (NCI/IWCLL), criteria.
  • --This includes previous documentation of:
  • Biopsy-proven small lymphocytic lymphoma/CLL
  • OR
  • Diagnosis of CLL according to the NCI/IWCLL criteria as evidenced by all of the following:
  • Peripheral blood monoclonal B cell population of greater than 5x109/L
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  • Immunophenotype consistent with CLL defined as:
  • The predominant population of lymphocytes share both B cell antigens [CD19, CD20 (typically dim expression), or CD23] as well as CD5 in the absence of other pan-T-cell markers (CD3, CD2, etc).
  • Clonality as evidenced by κ or λ light chain restriction (typically dim immunoglobulin expression)
  • Negative Fluorescence in situ hybridization (FISH) analysis for t(11;14)(IgH/CCND1) on peripheral blood or tissue biopsy (e.g. marrow aspirate), or negative immunohistochemical stains for cyclin D1 on involved tissue biopsy (e.g. marrow aspirate or lymph node biopsy).
  • Repeat testing of somatic mutations and FISH analysis must be performed by a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory after progression is noted from most recent line of therapy and within 6 months of screening. Primary CLL cells must harbor one of these abnormalities:
  • Somatic gene mutation testing shows mutation(s) in Tumor protein P53 (TP53), Ataxia-telangiectasia mutated (ATM), Splicing factor 3b subunit 1 (SF3B1), eukaryotic nuclear export protein exportin-1 (XPO1) and/or Protection of Telomeres Protein 1 (POT1)
  • Cytogenetic FISH analysis shows deletion 17p13 and/or deletion 11q22.3
  • Relapsed or refractory after at least 2 prior lines of therapy, and in the opinion of the treating Investigator are either not eligible for other approved therapies or no approved therapies are expected to have sustained therapeutic benefit.
  • Patient in need of treatment or change in treatment per iwCLL criteria.
  • --Patients on Bruton tyrosine kinase (BTK), Phosphoinositide 3-kinase inhibitor (PI3K) or B-cell lymphoma 2 (BCL2) inhibitors may enroll without meeting iwCLL criteria for treatment as long as there is clinical evidence of progression (i.e. increasing lymphocytosis, worsening anemia/thrombocytopenia attributable to CLL disease progression, increasing lymphadenopathy, or worsening patient symptoms) and require change in treatment at the discretion of the treating provider. Patients must still meet all other inclusion/exclusion criteria for enrollment including appropriate washout periods (5.2.2) and relapsed disease after 2 prior lines of therapy with no other approved therapies that are expected to have sustained therapeutic benefit (5.1.3).
  • Age ≥18 years
  • Eastern Cooperative Oncology Group (ECOG) performance status between 0-2
  • Expected life expectancy of at least 12 months per the investigator.
  • The following laboratory or clinical values obtained ≤ 42 days prior to enrollment:
  • Absolute neutrophil count ≥1000/µL (G-CSF support is allowed) unless documented bone marrow involvement of CLL
  • Platelets of ≥50K/µL unless documented bone marrow involvement of CLL
  • Creatinine Clearance (CrCl) ≥45 mL/minute as measured by a 24 hour urine collection or calculated by the Cockcroft-Gault Formula
  • Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) unless due to Gilbert's disease. For those patients with previous history of Gilbert's disease, a direct bilirubin should be performed and must be <1.5mg/dL.
  • SGOT (AST)/SGPT (ALT) ≤3.0 x the institutional ULN
  • Time from the start of the Q wave to the end of the T wave (QT) corrected for heart rate by Fridericia's cube root formula (QTcF) ≤470 msec
  • For patients with prolonged AT interval due to bundle branch block, a "corrected value" ≤470 msec and confirmation by cardiologist that patient is asymptomatic and that no other cardiac conduction or cardiac abnormality is present would pose any safety issues for the patient.
  • Recommended correction of QT for patients with bundle branch block are as follows: Patient's Q wave R wave and S wave complex (QRS) is 160 msec, and the measured QT is 510 msec. As the normal QRS is ~120 msec, subtract 120 msec from the measured QRS of the patient (160-120 = 40 msec) and then subtract this result from the measured QT (510-40=470 msec).
  • Pulse oximetry reading of ≥90% on room air
  • Able to adhere to study visit schedule and other protocol requirements
  • Patients must be able to swallow capsules
  • Patients must be able to receive xanthine oxidase inhibitor and/or rasburicase for tumor lysis syndrome prophylaxis.
  • Patients with a history of hepatitis B (surface antigen or core antibody-positive and polymerase chain reaction (PCR) positive) must take lamivudine or equivalent drug during study therapy and for one year after completion of all therapy. Patients on IVIG who are core antibody-positive but PCR negative are not mandated to take prophylaxis.
  • Patients who are HIV (human immunodeficiency virus) positive are eligible under the following circumstances:
  • Undetectable HIV viral load (laboratory value obtained within the last 6 months prior to enrollment)
  • CD4 count ≥200 (laboratory value obtained within the last 6 months prior to enrollment)
  • Actively taking antiretroviral therapy (ART)
  • Current ART therapy cannot have significant interactions with RP-3500 or Olaparib (Refer to Appendix 5). If current medications do interact, patients should receive alternative ART.
  • Recovery to baseline or ≤ Grade 1 CTCAE v5.0 from toxicities related to any prior cancer therapy, unless considered clinically not significant by the treating investigator.
  • Female patients capable of reproduction or males who have partners capable of reproduction must agree to the use of an effective contraceptive method during the course of the study and for 6 months following the completion of their last treatment.
  • Females of childbearing potential must have a negative serum β-Hcg pregnancy test result within 3 days of the first study dose. Female patients who are surgically sterilized or who are >45 years old and have not experienced menses for >2 years may have β-Hcg pregnancy test waived.

Who cannot join

  • Patients who are currently receiving any other investigational drug. Patients who are or have received therapies for the prevention, treatment or management of Corona Virus 19 (COVID-19) under the Food and Drug Administration (FDA) emergency use authorization are allowed to enroll.
  • Patients who have received:
  • Radiation or chemotherapy ≤2 weeks prior to registration.
  • Immunotherapy or targeted therapy ≤2 weeks prior to registration.
  • ---Patients currently on BCR pathway antagonists (i.e. BTK and PI3K inhibitors, etc) require a 2 day wash out period prior to starting combination therapy with RP-3500 and olaparib as these subjects progress quickly after treatment discontinuation.
  • Strong CYP3A inhibitors or inducers, p-glycoprotein inhibitors, or BCRP inhibitors within five half-lives or 14 days of registration, whichever is shorter (See Appendix 5).
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  • Prior ATR inhibitor use, but prior PARP inhibitor use for any reason is allowed on study.
  • Major surgery 4 weeks prior to C1D1 or who have not fully recovered from major surgery.
  • Evidence of active Richter's Transformation
  • Disease states requiring steroids (e.g. adrenal insufficiency, autoimmune conditions) are allowed as long as the steroid dose is ≤10mg of prednisone or equivalent dose of another steroid. Steroids premedications to prevent iodine contrast allergy for CT scans are allowed.
  • Patients who have undergone autologous stem cell transplant ≤4 weeks or allogeneic stem cell transplant ≤12 weeks prior to cycle 1 day 1 or have active graft-versus-host disease are excluded.
  • Patients who have active, clinically significant hepatic impairment (≥ moderate hepatic impairment according to the NCI/Child-Pugh classification)
  • Prior history of another malignancy except for the following:
  • Patients with current history of basal or squamous skin carcinoma, cervical carcinoma in situ, localized breast cancer requiring hormonal therapy, or localized prostate cancer (Gleason score <6) are allowed.
  • Previously treated malignancies (with chemotherapy, radiation, and/or surgery) currently deemed to have been in complete remission for at least 24 months.
  • Patients with active known central nervous system (CNS) involvement of CLL. Patients with a history of CNS CLL now in remission are eligible for the trial.
  • Patients with uncontrolled concurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, extensive bilateral interstitial lung disease, unstable angina pectoris, or psychiatric illness/social situations that would limit compliance with study requirements.
  • --Patients with a history of pneumonitis or pulmonary disease that could predispose them to development of Interstitial lung disease (ILD) and/or underlying respiratory conditions should be excluded.
  • Known prior severe hypersensitivity to RP-3500, olaparib, or any component in its formulations (NCI CTCAE v5.0 Grade ≥ 3).
  • Female patients who are pregnant or actively breast feeding
  • Patients with conditions significantly affecting gastrointestinal function including, but not limited to:
  • Significant resection of the stomach or small bowel
  • Symptomatic inflammatory bowel disease
  • Partial or complete bowel obstruction

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Huntsman Cancer Institute at the University of Utah

    Salt Lake City, Utah, 84112

Other trials in United States

About this study

Official title: A Phase Ib/II Trial of Combination RP-3500 and Olaparib in DNA Damage Repair Pathway Deficient Relapsed/Refractory Chronic Lymphocytic Leukemia

This is an open-label, multicenter, phase Ib/II study of the combination of RP-3500 and olaparib in Relapsed/Refractory Chronic Lymphocytic Leukemia (R/R CLL) patients with DDR deficiencies.

Read the detailed description

The Phase Ib part of the trial will seek to assess the Maximum Tolerated Dose (MTD) of camonsertib (RP-3500) in combination with olaparib. Given the potential overlapping toxicities of RP-3500 and olaparib, a keyboard phase I design, a novel Bayesian method that typically underestimates the MTD,61 will be employed. The target toxicity is 30% with an equivalence interval between 25-33% of patients. With an anticipated 3 dose levels (DL) and an option for a DL-1, up to 18 patients may be required to determine the MTD. A maximum of 12 patients will be treated at a DL.

The first 5 patients treated at the previous DL1 (camonsertib 40mg daily and olaparib 100mg two times a day (BID) dosing 3 days per week) determined that this dosing strategy may not be appropriate for R/R CLL patients and reduced dosing may be necessary to increase safety of the combination therapy. Therefore, the newly proposed DLs will seek to enroll an additional 18 patients.

After completion of the phase Ib portion and assignment of the recommended phase 2 dose (RP2D), continuous enrollment of patients may commence into the phase II dose expansion portion. All patients enrolled at the RP2D during the phase Ib dose-escalation portion of the trial can be carried over into the phase II analysis. The maximum number of patients that can be carried over from the dose escalation to the dose-expansion portion is 12.

The phase II dose expansion will consist of two separate cohorts of subjects: an enrichment cohort and a cohort for all other eligible subjects. All subjects enrolled into the enrichment cohort must have a del(11q) and/or ATM mutation. Eight subjects will be enrolled into the enrichment cohort and 16 will be enrolled into the second cohort for a total phase II cohort of 24 patients.

Being tested
RP-3500, Olaparib
Medical subject headings
Leukemia, Lymphocytic, Chronic, B-Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • RP-3500Drug

    RP-3500 is a highly potent and selective Ataxia telangiectasia and Rad3 related inhibitor (ATRi) and has demonstrated significant preclinical activity.

  • OlaparibDrug

    Olaparib is an oral poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi) that inhibits PARP's function by competitively binding to the Nicotinamide adenine dinucleotide (NAD+) binding site, which PARP requires as a cofactor to operate.

Study groups in NCT05405309
Study groupRoleWhat they receive
Phase Ib: Dose Level -1ExperimentalTo assess the MTD of RP-3500 in combination with olaparib. Patients will receive RP-3500 40mg daily and olaparib 100mg BID. Both drugs are given with intermittent dosing of 2 days per week and each cycle is 21 days.
Receives: Drug: RP-3500; Drug: Olaparib
Phase Ib: Dose Level 1ExperimentalTo assess the MTD of RP-3500 in combination with olaparib. Patients will receive RP-3500 50mg daily and olaparib 100mg BID. Both drugs are given with intermittent dosing of 2 days per week and each cycle is 21 days.
Receives: Drug: RP-3500; Drug: Olaparib
Phase Ib: Dose Level 2ExperimentalTo assess the MTD of RP-3500 in combination with olaparib. Patients will receive RP-3500 80mg daily and olaparib 100mg BID. Both drugs are given with intermittent dosing of 2 days per week and each cycle is 21 days.
Receives: Drug: RP-3500; Drug: Olaparib
Phase Ib: Dose Level 3ExperimentalTo assess the MTD of RP-3500 in combination with olaparib. Patients will receive RP-3500 80mg daily and olaparib 150mg BID. Both drugs are given with intermittent dosing of 2 days per week and each cycle is 21 days.
Receives: Drug: RP-3500; Drug: Olaparib
Phase II: Dose Expansion Enrichment CohortExperimentalSubjects enrolled into the enrichment cohort must have a del(11q) and/or ATM mutation.
Receives: Drug: RP-3500; Drug: Olaparib
Phase II: Dose Expansion Eligible Subjects CohortExperimentalCohort will include all other eligible subjects for Dose Expansion.
Receives: Drug: RP-3500
Phase Ib (prior to Aug2023 amendment): Original Dose Level 1ExperimentalTo assess the MTD of RP-3500 in combination with olaparib. Before the Aug2023 amendment, patients enrolled at Dose Level 1 received RP-3500 40mg daily and olaparib 100mg BID. Both drugs were given with intermittent dosing of 3 days per week and each cycle was 28 days.
Receives: Drug: RP-3500; Drug: Olaparib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Maximum Tolerated Dose (MTD) of Camonsertib (RP-3500) in Combination With Olaparib

    This outcome will report the number of patients who experienced a Dose-Limiting Toxicity (DLT) in Phase Ib Dose Level 1, Phase Ib Dose Level 2, Phase Ib Dose Level 3, and Phase Ib Dose Level -1 during the DLT window (Cycle 1 Day 1 to Cycle 1 Day 21).

    A keyboard phase I design was employed; the target toxicity was 30% with an equivalence interval between 25-33% of patients. The first 5 patients were treated at DL-1 (camonsertib 40mg daily and olaparib 100mg BID dosing 3 days per week).

    Measured: up to 28 days after initiation of study drug

  2. Overall Response

    This outcome will assess the overall responseof combination RP-3500 and olaparib. Overall response is defined by the count of subjects achieving any confirmed partial (PR) and complete response (CR) as assessed by 2018 International Working Group on Chronic Lymphocytic Leukemia (iwCLL) response criteria.

    Subjects without a baseline/screening tumor assessment or at least one on-treatment assessment will be considered non-responders.

    Measured: up to 85 Days after initiation of study drug

Secondary outcomes (4)

  1. Adverse Events (AE) by Grade

    This outcome measure will assess the safety and tolerability of RP-3500 and olaparib.

    The severity of AEs was assessed using CTCAE v5.0 criteria, a 1-5 scale with higher numbers indicating greater severity. Grade 1 indicates "mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated" and Grade 5 indicates "death related to AE".

    The severity of adverse hematologic adverse events was assessed using the 2018 IWCLL grading scale. Grade 0 indicates "≤10% decrease in platelets (PLT) or hemoglobin (Hb) from baseline and ≥2 absolute neutrophil count (ANC)" and Grade 4 indicates "≥75% decrease in PLT or Hb from baseline and <0.5 ANC"

    This outcome measure will report the count of participants who experienced each AE grade. Subjects were monitored for adverse events from the start of treatment until 28 days after the last dose of the study drug.

    Measured: up to 28 days after the last dose of study treatment (up to 113 days after initiation of study drug)

  2. Progression-free Survival (PFS)

    Progression-free survival (PFS) as defined as the time from study drug initiation to the time documented disease progression (as assessed by 2018 iwCLL criteria) or death from any cause. Patients were followed for PFS until progression of disease was noted or death, whichever occurred first.

    This outcome will report the median PFS with 95% confidence intervals.

    Measured: up to 15 months from initiation of study treatment

  3. Overall Survival (OS)

    This outcome will assess OS as defined as the time between treatment initiation and death of any cause.

    Subjects were followed for OS from the initiation of therapy until death from any cause or until the study was terminated. Subjects lost to follow-up or refused follow-up were censored at the time of the last known follow-up.

    This outcome will report the median OS with 95% confidence intervals.

    Measured: up to 21 months after study registration

  4. Duration of Response (DoR) as Defined as the Interval of Time From the Date of Initial Documented Response (PR or Better as Per 2018 iwCLL Criteria for Response) to the Time of Progression.

    DoR is defined as the interval of time from the date of the initial documented response (PR or better as per 2018 iwCLL criteria for response) to the time of progression.

    Patients would be followed for DoR from the date of the initial documented response until progression of disease was noted or death, whichever occurred first.

    This outcome would have reported the median DoR with 95% confidence intervals.

    Measured: up to 21 months after initiation of study treatment.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted6 Jun 2022
  2. Study start23 Sep 2022
  3. Primary completion24 Oct 2023
  4. Study completion10 Jan 2025

Why it stopped: This study was terminated due to sponsor de-activation of all programs associated with RP-3500 (camonsertib).

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Sequential
Masking
None (open label)
Enrolment
5 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05405309
Sponsor's protocol ID
HCI141431
Acronym
CORONADO CLL
Status last verified
May 2025
First submitted
31 May 2022
Last updated
3 Jun 2025
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing RP-3500 and Olaparib in people with Chronic Lymphocytic Leukemia, run by University of Utah at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 41 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 3 Jun 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 3 Jun 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum Tolerated Dose (MTD) of Camonsertib (RP-3500) in Combination With Olaparib (time frame: up to 28 days after initiation of study drug). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05405309.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Jun 2025.

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